Lunsumio
mosunetuzumab · CD20 x CD3US, Republic of Korea, Canada: dose-escalation part (Group A) of study GO29781 in patients with R/R B-cell NHL
Imdelltra: what was done before first-in-human, and what came after?
tarlatamab · DLL3 x CD3
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Imdelltra don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: HNSTD 4500 µg/kg (maximum feasible dose); lymphocyte decreases, transient heart rate increase, pituitary mononuclear infiltrates (FDA multi-discipline review, p. 65)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month (13-week) weekly IV cynomolgus monkey study; recovery phase not stated
“Tarlatamab: 3-Month Intravenous Toxicology Study in the Cynomolgus Monkey / Study Number: 122516 /eCTD location: Module 4.2.3.2 Key Drug-related Adverse Findings No adverse effects on any toxicology or safety pharmacology parameters evaluated at up to the high dose of 4500 µg/kg weekly for 3 months.”
Pivotal GLP studies
GLP cynomolgus 28-day (with 28-day recovery) and 3-month weekly IV studies up to 4500 µg/kg; non-GLP 10-day study; mouse surrogate 1-month
“The nonclinical safety assessment of tarlatamab was based on a 10-day exploratory as well as 28-day GLP and 3-month GLP repeat-dose IV toxicology studies with once weekly doses of up to 4500 µg/kg.”
DART package
Species: DART
Mouse EFD study with surrogate muS757
“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”
Reproductive & developmental
Mouse EFD study with surrogate muS757 (GD6, GD13): no maternal or EFD toxicity up to 4500 µg/kg; placental transfer; no fertility studies
“Two administrations of a tarlatamab surrogate, mus757, that binds mouse CD3 and DLL3, to pregnant mice on gestational days (GD) 6 and GD 13 did not result in maternal toxicity or embryo-fetal development toxicity at doses ≤4500 µg/kg.”
PPND / ePPND: when
No PPND study; reproduction testing limited to mouse EFD with murine surrogate
“Animal reproduction studies have not been conducted with tarlatamab-dlle. In an embryo-fetal developmental toxicity study, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Carcinogenicity timing
Not required (none conducted or planned per ICH S9; FDA agreed)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010). The FDA’s Assessment: The FDA agrees.”
Same question, other multispecifics
Rybrevant
amivantamab · EGFR x METUS and ex-US (Australia, Canada, China, France, Japan, Korea, Spain, Taiwan, UK): first-in-human dose escalation/expansion in advanced NSCLC
Talvey
talquetamab · GPRC5D x CD3US and ex-US (Belgium, France, Germany, Israel, Netherlands, Poland, Korea, Spain): first-in-human dose escalation/expansion
Tecvayli
teclistamab · BCMA x CD3US and ex-US (Belgium, Canada, France, Germany, Italy, Netherlands, Spain, Sweden, UK): first-in-human study
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)North America and South Korea: first-in-human study ZWI-ZW25-101 in HER2-expressing cancers
Bizengri
zenocutuzumab · HER2 x HER3Not stated in public reviews
Blincyto
blinatumomab · CD19 x CD3Not stated in public reviews
Columvi
glofitamab · CD20 x CD3Not stated in public reviews
Elrexfio
elranatamab · BCMA x CD3Not stated in public reviews
Epkinly
epcoritamab · CD20 x CD3Not stated in public reviews
Hemlibra
emicizumab · FIXa x FXNot stated in public reviews
Kimmtrak
tebentafusp · CD3 x gp100 (TCR fusion)Not stated in public reviews
Korjuny
catumaxomab · EpCAM x CD3Not stated in public reviews
Lynozyfic
linvoseltamab · BCMA x CD3Not stated in public reviews
Ordspono
odronextamab · CD20 x CD3Not stated in public reviews
Removab
catumaxomab · EpCAM x CD3Not stated in public reviews
Vabysmo
faricimab · VEGF-A x Ang-2Not stated in public reviews